Systemic p47phox deficiency suppresses DVT formation by inhibiting the PAC-1/FNG/MAC-1 signaling axis, thereby affecting platelet-neutrophil interactions and NET generation, and by protecting endothelial cells through amelioration of ROS-mediated mitochondrial dysfunction.
p47phox knockout mice exhibited reduced thrombus incidence, weight, and length compared to wild-type mice in a DVT model.
DVT patients showed increased p47phox mRNA and protein expression in neutrophils compared to healthy volunteers.
p47phox deficiency reduced NET formation markers in thrombi and plasma of knockout mice.
Platelets from p47phox-/- mice exhibited reduced integrin αIIbβ3 activation and decreased fibrinogen binding capacity.
p47phox deficiency reduced MAC-1 activation on neutrophils, disrupting platelet-neutrophil interactions through the PAC-1/FNG/MAC-1 signaling axis.
p47phox knockdown in human umbilical vein endothelial cells (HUVECs) decreased ROS generation and improved mitochondrial function.
p47phox deficiency was associated with altered coagulation parameters consistent with reduced thrombotic tendency.
This research suggests that a protein called p47phox, a key component of an enzyme complex that produces reactive oxygen species (ROS, or cellular 'rust'), plays an important role in the formation of deep vein thrombosis (DVT) — dangerous blood clots that typically form in the legs. The researchers found that DVT patients had higher levels of p47phox in their immune cells (neutrophils) compared to healthy people. When they studied mice that were genetically engineered to lack p47phox, these animals developed fewer and smaller blood clots, pointing to p47phox as a significant driver of clot formation. The study identified several ways p47phox promotes clotting. First, it activates a chain of molecular signals (the PAC-1/FNG/MAC-1 axis) that causes platelets — the small blood cells responsible for clotting — to become activated and stick to neutrophils (a type of immune cell). This interaction triggers neutrophils to release sticky, web-like structures called neutrophil extracellular traps (NETs), which are known to promote clotting. When p47phox was absent, this entire cascade was dampened: fewer NETs were released, and platelet-neutrophil interactions were reduced. Second, p47phox in blood vessel wall cells (endothelial cells) produces ROS that damage the cells' energy-producing organelles (mitochondria). When p47phox was reduced in these cells, the mitochondria functioned better, producing more energy and maintaining healthier membrane function. This research suggests that p47phox could be a promising target for future therapies aimed at preventing or treating DVT. By blocking p47phox, it may be possible to simultaneously reduce harmful immune-cell activity, protect blood vessel walls, and decrease clot formation. However, the authors caution that while the study identified these multiple mechanisms, the specific contributions of each individual cell type still need further investigation, and the findings need to be validated before any clinical applications could be considered.
Wang Y, Wan Y, Zhao Y, Wang X. (2026). Knockout of p47phox inhibits deep vein thrombosis by regulating the PAC-1/FNG/MAC-1 signaling axis and ameliorating mitochondrial dysfunction.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1836884